Calcitonin gene-related peptide in migraine: the pathogenetic factor and therapeutic target (review)

O.Ye. Dubenko


Migraine is a common neurological disorder that spreads in all regions in the world. Recent researches show that migraine is a complex condition involving central and peripheral trigeminovascular system, brainstem, thalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In migraine, CGRP peptide is released from trigeminal ganglia cells that cause the release of inflammatory mediators and dilatation of cranial blood vessels. The vasodilation and neurogenic inflammation further increase activation of the sensory trigeminal fibers, perpetuate the release of vasoactive peptides including CGRP, and modulate transmission of pain impulses to the brain. In addition, in acute attack, the spread of cortical depression directly activate the peripheral trigeminal nociceptors, which release nitric oxide and CGRP. CGRP is one of the most potent endogenous vasodilators, it intravenous administration induces migraine-like headache. Other function of CGRP is transmission of nociceptive information from intracranial blood vessels to the central nervous system. At present, CGRP remains the most actively evaluated target in migraine drug research. Triptans remain the gold standard of acute migraine attack therapy and inhibited release of CGRP from trigeminal sensory neurons. The paper reviews the recent findings on the development of CGRP receptor antagonists for acute treatment of episodic migraine and several monoclonal antibodies for migraine prevention. Few CGRP antagonists used small molecules and named gepants were clinically tested and demonstrated clinically efficacy but its development was discontinued due to liver toxicity. Humanized calcitonin gene-related peptide receptor monoclonal antibodies were found to be effective and safe for preventive treatment of episodic migraine and chronic migraine in randomized, double-blind, placebo-controlled trials. In episodic migraine, anti-CGRP-receptor antibody erenumab was evaluated in phase 3 trials ARISE and STRIVE. Erenumab statistically significantly reduced migraine incidence, and greater proportion of patients achieved ≥ 50% reduction of monthly migraine days compared to placebo. Fremanezumab is a humanized monoclonal antibody that selectively blocks CGRP binding to its receptor. It was effective and well-tolerated in preventing episodic migraine for 3 months of placebo-controlled phase 2 studies. In chronic migraine, the efficacy of erenumab was evaluated in 12-week trial. Results showed a significant reduction in the number of monthly migraine days and the intake of migraine-specific medications versus placebo. Humanized anti-CGRP antibody eptinezumab intravenous infusion also showed a significant reduction in heada­che impact. Anti-CGRP monoclonal antibodies can be a new generation of medication in migraine preventive treatment.


calcitonin gene-related peptide; episodic migraine; chronic migraine; monoclonal antibodies


Manzoni G.C., Stovner L.J. Epidemiology of headache // Handb. Clin. Neurol. — 2010. — Vol. 97. — P. 3-22.

Goadsby P.J., Lipton R.B., Ferrari M.D. Migraine — Current understanding and treatment // N. Engl. J. Med. — 2002. — Vol. 346 — P. 257-270.

Charles A. The evolution of a migraine attack — a review of recent evidence // Headache. — 2013. — Vol. 53. — P. 413-419.

De Tommaso M., Ambrosini A., Brighina F., Coppola G., Perrotta A. et al. Altered processing of sensory stimuli in patients with migraine // Nat. Rev. Neurol. — 2014. — Vol. 10. — P.144-155.

Goadsby P.J. The vascular theory of migraine — a great story wrecked by the facts // Brain. — 2009. — Vol. 132. — P. 6-7.

Levy D., Burstein R. The vascular theory of migraine: leave it or love it? // Ann. Neurol. — 2011. — Vol. 69. — P. 600-601.

Charles A. Migraine is not primarily a vascular disorder // Cephalalgia. — 2012. — Vol. 32. — P. 431-432.

Goadsby P.J., Charbit A.R., Andreou A.P., Akerman S., Holland P.R. Neurobiologe of migraine // Neuroscience. — 2009. — Vol. 161. — P. 327-341.

Noseda R., Burstein R. Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain // Pain. — 2013. —

Vol. 154(Suppl. 1). — P. 1-21.

Lee D.M., Wilcox S.L., Hodkinson D. et al. Thalamic and Thalamocortical Structure in Migraine // Headache. — 2017. — Vol. 57(Suppl. 3). — P. 122-123.

Karatas H., Erdener S.E., Gursoy-Ozdemir Y. et al. Sprea­ding depression triggers headache by activating neuronal Pan1 channals // Science. — 2013. — Vol. 339. — P. 1092-1095.

Buzzi M.G., Moskowitz M.F. The pathophysiology of migraine: Year 2005 // J. Headache Pain. — 2005. — Vol. 6. — P. 105-111.

Kisson N.R., Cutrer F.M. Аura and Other Neurologic Dysfunction in or with Migraine // Headache. — 2017. — Vol. 57, № 7. — P. 1179-1194.

Eftekhari S., Salvatore C.A., Calamari A., Kane S.A., Tajti J., Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion // Neuroscience. — 2010. — Vol. 169. — P. 683-696.

Villalon C.M., Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs // Pharmacol. Ther. — 2009. — Vol. 124. — P. 309-323.

Tfelt-Hansen P., Le H. Calcitonin gene-related peptide in blood: Is it increased in the external jugular vein during migraine and cluster headache? A review // J. Headache Pain. — 2009. —

Vol. 10. — P. 137-143.

Ho T.W., Edvinsson L., Goadsby P.J. CGRP and its receptors provide new insights into migraine pathophysiology // Nat. Rev. Neurol. — 2010. — Vol. 6. — P. 573-582.

Cernuda-Morollón E., Larrosa D., Ramón C., Vega J., Martínez-Camblor P., Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine // Neurology. —

— Vol. 81. — P. 1191-1196.

Hansen J.M., Hauge A.W., Olesen J., Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura // Cephalalgia. — 2010. — Vol. 30. — P. 1179-1186.

Durham P.L. CGRP receptor antagonists - A fresh approach to migraine therapy? // N. Engl. J. Med. — 2004. — Vol. 350. — Р. 1073-1074.

Recober A., Russo A.F. Calcitonin gene-related peptide: An update on the biology // Curr. Opin. Neurol. — 2009. — Vol. 22. — P. 241-246.

Feuerstein G., Willette R., Aiyar N. Clinical perspectives of calcitonin gene related peptide pharmacology // Can. J. Physiol. Pharmacol. — 1995. — Vol. 73. — P. 1070-1074.

Brain S.D., Grant A.D. Vascular actions of calcitonin gene-related peptide and adrenomedullin // Physiol. Rev. — 2004. — Vol. 84. — P. 903-934.

Brain S.D., Williams T.J., Tippins J.R., Morris H.R., MacIntyre I. Calcitonin generelated peptide is a potent vasodilator // Nature. — 1985. — Vol. 313. — P. 54-56.

Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine // Neurology. — 1993. — Vol. 43(Suppl. 3). — Р. 16-20.

Benarroch E.E. CGRP: Sensory neuropeptide with multiple neurologic implications // Neurology. — 2011. — Vol. 77. — P. 281-287.

Raddant A.C., Russo A.F. Calcitonin gene-related peptide in migraine: Intersection of peripheral inflammation and central modulation // Expert Rev. Mol. Med. — 2011. — Vol. 13. — Р. 36.

Eftekhari S., Edvinsson L. Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level // BMC Neurosci. — 2011. — Vol. 12. — P. 112.

Sun R.Q., Lawand N.B., Willis W.D. The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin // Pain. — 2003. — Vol. 104. — P. 201-208.

Bernstein C., Burstein R. Sensitization of the trigeminovascular pathway: Perspective and implication to migraine pathophysiology // J. Clin. Neurol. — 2012. — Vol. 8. — P. 89-99.

Louter M.A., Bosker J.E., van Oosterhout W.P. et al. Cutaneus allodynia as a predictor of migraine chronification // Brain. — 2013. — Vol. 136. — P. 3489-3496.

Lipton R.B., Munjal S., Buse D.S. et al. Allodynia is accosiated with initial and sustained response to acute migraine treatment: Result from the American Migraine Prevalence and Prevention Study //

Headache. — 2017. — Vol. 57, № 7. — P. 1026-1040.

Recober A., Kuburas A., Zhang Z., Wemmie J.A., Anderson M.G., Russo A.F. Role of calcitonin generelated peptide in light-aversive behavior: Implications for migraine // J. Neurosci. — 2009. —

Vol. 29. — P. 8798-8804.

Mason B.N., Kaiser E.A., Kuburus A. et al. Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms // The Journal of Neuroscience. — 2017. —

Vol. 37(1). — P. 204-216.

Bigal M.E., Walter S., Rappoport A.M. Calcitonin Gene-Related Peptide (CGRP) and Migraine Current Understanding and State of Development // Headache. — 2013. — Vol. 53. — P. 1230-1244.

Loder E. Triptan therapy in migraine // N. Engl. J. Med. — 2010. — Vol. 363. — P. 63-70.

Asghar M.S., Hansen A.E., Kapijimpanga T. еt al. Dilatation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers // Neurology. — 2010. — Vol. 75. — P. 1520-1526.

Durham P.L., Russo A.F. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug // J. Neurosci. — 1999. — Vol. 19. — P. 3423-3429.

Durham P.L., Dong P.X., Belasco K.T., Kasperski J., Gie­rasch W., Edvinsson L. et al. Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons // Brain Res. — 2004. — Vol. 997. — P. 103-110.

Durham P.L., Cady R., Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy // Headache. —

— Vol. 44. — P. 35-43.

Sinclair S.R., Kane S.A., Van der Schueren B.J. et al. Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974) // Br. J. Clin. Pharmacol. — 2010. — Vol. 69. — P. 15-22.

Silberstein S.D. Emerging target-based paradigms to prevent and treat migraine // Clin. Pharmacol. Ther. — 2013. — Vol. 93. — P. 78-85.

Russo A.F. Calcitonin gene-related peptide (CGRP): A new target for migraine // Ann. Rev. Pharmacol. Toxicol. — 2015. — Vol. 55. — P. 533-552.

Olesen J., Diener H.C., Husstedt I.W. et al. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine // N. Engl. J. Med. — 2004. — Vol. 350. —

P. 1104-1110.

Ho T.W., Mannix L.K., Fan X. et al. Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine // Neurology. — 2008. — Vol. 70. — P. 1304-1312.

Ho T.W., Ferrari M.D., Dodick D.W. et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment trial // Lancet. — 2008. — Vol. 372. — P. 2115-2123.

Ho T.W., Connor K.M., Zhang Y., Pearlman E., Koppenhaver J., Fan X., Lines C., Edvinsson L., Goadsby P.J., Michelson D. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention // Neurology. — 2014. — Vol. 83. — P. 958-966.

Hewitt D.J., Aurora S.K., Dodick D.W. et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine // Cephalalgia. — 2011. — Vol. 31. — P. 712-722.

Diener H.C., Barbanti P., Dahlof C., Reuter U., Habeck J., Podhorna J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: Results from a phase II study // Cephalalgia. — 2011. — Vol. 31. — P. 573-584.

Dodick D.W., Goadsby P.J., Spierings E.L., Scherer J.C., Sweeney S.P., Grayzel D.S. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study // Lancet Neurol. — 2014. — Vol. 13. — P. 885-892.

Mould D.R., Sweeney K.R. The pharmacokinetics and pharmacodynamics of monoclonal antibodies — mechanistic modeling applied to drug development // Curr. Opin. Drug. Discov. Devel. — 2007. — Vol. 10. — P. 84-96.

Goadsby P.J., Reuter U., Bonner J. еt al. Phase 3, rando­mized, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab (AMG 334) in migraine prevention: primary result of the STRIVE Trial // Eur. Journal of Neurol. — 2017. — Vol. 24(Suppl. 1). — P. 117.

Ashina M., Dodick D., Kudrow D. et al. A Phase 3, rando­mized, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab in migraine prevention: Primary result of the ARISE Trial // Eur. Journal of Neurol. — 2017. — Vol. 24(Suppl. 1). — P. 470.

Noble R., Aycardi E., Bigal M., McDonald M., Loupe P. Fremanezumab increases the maximum number of consecutive heada­che free days for patients with high frequency episodic migraine //

Headache. — 2017. — Vol. 57(Suppl. 3). — P. 185.

Aycardi E., Bigal M., McDonald M., Noble R., Loupe R. Fremanezumab (formerly TEV-48125) reduces headache pain within the first week of beginning treatment in the phase 2 episodic migraine study // Headache. — 2017. — Vol. 57(Suppl. 3). — P. 129-130.

Headache Classification Subcommittee of the International Headache Society (IHS). The International Classification of Heada­che Disorders, 3rd еdition (beta version) // Cephalalgia. — 2013. — Vol. 33. — P. 629-808.

Lipton R.B., Varon S.F., Grosberg B. et al. Onabotulinumtoxin. A improves quality of life and reduces impact of chronic migraine // Neurology. — 2011. — Vol. 77. — P. 1465-1472.

Tepper S.J., Dolezil D., Ashina M. et al. A phase 2 randomi­zed, double-blind, placebo-controlled study to evaluate the efficacy and safety of Erenumab (AMG 334) in chronic migraine prevention //

Headache. — 2017. — Vol. 57(Suppl. 3). — P. 130.

Tepper S.J., Reuter U., McAllister P.J. et al. Early Onset of efficacy in a phase 2 clinical trial of erenumab in patients with chronic migraine // Headache. — 2017. — Vol. 57(Suppl. 3). — P. 193.

Reuter U., Brandes J., Dolezil D. et al. Efficacy of erenumab (AMG 334) in patients with chronic migraine in Noth America and Europe: Subgroup analysis of a phase 2, randomized, double-blind, placebo-controlled study // Eur. Journal of Neurol. — 2017. — Vol. 24(Suppl. 1). — P. 548.

Diener H.-C., Ashina M., Brandes J. et al. Efficacy of erenumab for the treatment of patients with chronic migraine in pre­sence of medication overuse // Eur. Journal of Neurol. — 2017. — Vol. 24(Suppl. 1). — P. 472.

Smith J., Dodick D.W., Goadsby P.J. et al. Randomized, double-blind, placebo-controlled trial of ALD403 (eptinezumab), an anti-CGRP monoclonal antibody for the prevention of chronic migraine // Headache. — 2017. — Vol. 57(Suppl. 3). — P. 130.

Lipton R.B., Dodick D.W., Goadsby P.J. et al. Respon­ders to ALD403 (eptinezumab) show significant reduction in heada­che impact at weeks 4 through 12 following a single infusion in chronic migraine // Headache. — 2017. — Vol. 57(Suppl. 3). — P. 176-177.



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